Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease

Atherosclerotic renovascular disease (ARD) is an increasinglyimportant cause of renal failure. However, important featuresof the clinical presentation are not fully described, and theoutcome after intervention by angioplasty remains controversial.Ninety-four patients with ARD diagnosed at angiography werereviewed. Twenty-four patients were diabetic. Thirty-nine patientshad unilateral renal artery stenosis or occlusion (group A),28 had bilateral stenosis (group B), and 27 had unilateral occlusionplus contralateral occlusion or stenosis (group C), Two yearsafter presentation, actuarial patient survival was 96%, 74.3%and 47.1% in groups A, B and C, respectively (p<0.001 forall differences); actuarial renal survival in surviving patientswas 97.3%, 82.4% and 44.7%, respectively (p<0.001 for alldifferences). Percutaneous transluminal balloon angioplasty(PCTA) was performed in 74 patients. Renal function improvedin only a minority of cases, but was stable in 73% of nondiabeticpatients 12 months after PCTA. Angioplasty was less effectivein diabetic subjects, with only 53.3% having stable renal functionat 12 months follow-up. Renal and patient survival were stronglyrelated to the initial angiographic findings. In nondiabeticsubjects, PCTA resulted in stabilization of renal function forat least one year in nearly threequarters of cases, which suggestsa benefit from intervention in this disease whose natural historyis otherwise of progression.     

Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-α) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-α production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77 059) and a 4 arylpyrrolidinone (rolipram). we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-α production in vitro in sodium periodate-elicited murine macrophages (IC₅₀s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-α induced by a subtethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 μg/mouse) injection of LPS, serum TNF-α levels in mice peaked sharply, reaching concentrations of 3–12 ng/ ml 90 min after injection. In this sublethal LPS assay, CP-77 059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC₅₀S for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77 059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-α levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 μg of LPS/mouse Is necessary for serum TNF-α elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-α and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-α response (without a serum TNF-α elevation), rolipram significantly inhibited paw swelling as well as localized TNF-α levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-α elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-α production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-α has been postulated to be a contributing factor in the pathology of the disease.     

A Randomized‐Controlled Pilot Study Comparing ICD Implantation with and Without Intraoperative Defibrillation Testing in Patients with Heart Failure and Severe Left Ventricular Dysfunction: A Substudy of the RAFT Trial

Comparing ICD Implantation with and Without Intraoperative Defibrillation Testing. Introduction: The need to perform defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion is controversial. In the absence of randomized trials, some regions now perform more than half of ICD implants without DT. Methods: During the last year of enrolment in the Resynchronization for Ambulatory Heart Failure Trial, a substudy randomized patients to ICD implantation with versus without DT. Results: Among 252 patients screened, 145 were enrolled; 75 randomized to DT and 70 to no DT. Patients were similar in terms of age (65.9 ± 9.3 years vs 67.9 ± 8.9 years); LVEF (24.7 ± 4.6% vs 23.6 ± 4.6%), QRS width (154.8 ± 23.5 vs 155.8 ± 23.6 ms), and history of atrial fibrillation (5% vs 6%). All 68 patients in the DT arm tested according to the protocol achieved a successful DT (≤25 J); 96% without requiring any system modification. No patient experienced perioperative stroke, myocardial infarction, heart failure (HF), intubation or unplanned ICU stay. The length of hospital stay was not prolonged in the DT group: 20.2 ± 26.3 hours versus 21.3 ± 23.0 hours, P = 0.79. One patient in the DT arm had a failed appropriate shock and no patient suffered an arrhythmic death. The composite of HF hospitalization or all‐cause mortality occurred in 10% of patients in the no‐DT arm and 19% of patients in the DT arm (HR = 0.53, 95% CI: 0.21–1.31, P = 0.14). Conclusions: In this randomized trial, perioperative complications, failed appropriate shocks, and arrhythmic death were all uncommon regardless of DT. There was a nonsignificant increase in the risk of death or HF hospitalization with DT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1313‐1316, December 2012)     

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XVII: ANTICHOLINERGIC PREMEDICANTS

The effects of premedication with the anticholinergic drugsatropine, hyoscine and glycopyrronium when administered by oraland i.m. routes have been evaluated in patients undergoing minorsurgery and compared with a placebo-using a double-dummy double-blindtechnique. Although the mouths of those patients who receivedadequate doses of anticholinergic drugs were dry, subjectivelyand observed, as compared with those who received a placebo,the overall course of anaesthesia did not appear to be different.Of the three drugs atropine seemed to be absorbed best followingoral administration. Equally effective oral and i.m. doses ofatropine were considered to be 2.0 and 1.0 mg respectively;of hyoscine 1.0 and 0.25–0.5 mg. The appropriate doseof glycopyrronium was 0.2 mg i.m. The routine use of anticholinergicdrugs in preanaesthetic medication in minor surgery appearsto be unnecessary.     

P-selectin antagonism reduces thrombus formation in humans

Summary.  Background:  Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. Aim:  To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans. Methods and Results:  In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2  m ) and high-dose (20  m ) PSI-697 and the glycoprotein IIb–IIIa receptor antagonist tirofiban (50 ng mL⁻¹) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb–IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2  m ) reduced total thrombus area by 14% ( P  = 0.04) and 30% ( P  = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20  m ), PSI-697 reduced total thrombus area by 18% ( P  = 0.0094) and 41% ( P  = 0.0008) in the low-shear and high-shear chambers, respectively. Conclusions:  P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.     

Combined Antiplatelet Therapy in Atrial Fibrillation:

Atrial fibrillation (AF), the most commonly encountered cardiac rhythm disorder, affects approximately 1% of the general population and is associated with serious complications, most notably ischemic stroke. AF-associated stroke occurs at an annual rate of 4.5%. Anticoagulation therapy with warfarin has been demonstrated in randomized controlled trials to reduce the risk for AF-related stroke by two thirds, but warfarin therapy is markedly underused in clinical practice because of its narrow therapeutic window and its implications on quality of life. This article reviews the present knowledge and potential future research avenues for the role of antiplatelet therapy in AF as an alternative to anticoagulation with warfarin for prevention of AF-associated stroke. Antiplatelet therapy recently has been shown to be protective against thrombotic events related to blood stasis. There is ample evidence from experimental and clinical studies that a combination of different antiplatelet agents may increase antithrombotic efficacy compared to monotherapy. Accordingly, a series of randomized controlled trials (ACTIVE [Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events]) has been designed to vigorously examine the role of combined antithrombotic therapy for prevention of vascular events, including stroke in high-risk AF patients. The ACTIVE program began patient enrollment in spring 2003. (J Cardiovasc Electrophysiol, Vol. 14, pp. S60-S63, September 2003, Suppl.)